Canadian Journal of Cardiology 35 (2019) 288e298
Review
Pulmonary Hypertension in HIV
Binaya Basyal, MD,a Harish Jarrett, MD,a,b and Christopher F. Barnett, MD, MPHa,b
a
MedStar Heart and Vascular Institute, Washington Hospital Center, Washington, DC, USA
b
MedStar Georgetown University Hospital, Washington, DC, USA
ABSTRACT
Human immunodeficiency viruseassociated pulmonary arterial hy-
pertension (HIV-PAH) is important to recognize given its association
with significant morbidity and mortality. With the introduction of anti-
retroviral therapy, the focus of disease management has largely shif-
ted from treating immunodeficiency-related opportunistic infections to
managing chronic cardiopulmonary complications. Symptoms are
nonspecific, and a high index of clinical suspicion is needed to avoid
significant delay in the diagnosis of HIV-PAH. Although several viral
proteins have been implicated in the pathogenesis of HIV-PAH, the
exact mechanism remains uncertain. Further studies are needed to
elucidate precise pathogenic mechanisms, early diagnostic tools, and
novel therapeutic targets to improve prognosis of this severe
complication.
Human immunodeficiency viruseassociated pulmonary arte-
rial hypertension (HIV-PAH) was first described in 1987 by
Kim and Factor1 in an HIV-infected patient with haemophilia
and membranoproliferative glomerulonephritis. Since then, it
has become an increasingly recognized complication of HIV
infection.2 With the introduction of antiretroviral therapy
(ART), survival of HIV-infected patients has markedly
improved with less deaths from consequences of immunode-
ficiency and opportunistic infections.3 HIV has gradually
become a chronic condition, and long-term cardiopulmonary
complications including HIV-PAH have emerged as the pri-
mary source of morbidity and mortality.4,5
Pulmonary hypertension (PH) has historically been defined
hemodynamically by a mean pulmonary artery pressure
(mPAP)
25 mm Hg measured during right heart cathe-
terization (RHC) and PAH by an mPAP
25 mm Hg and a
pulmonary artery wedge pressure (PAWP) of  15 mm Hg.6
However, it is important to note that the recommendations
Received for publication December 11, 2018. Accepted January 17, 2019.
Corresponding author: Dr Christopher F. Barnett, MedStar Heart and
Vascular Institute, 110 Irving St. NW, Washington, DC 20010, USA. Tel.:
þ1-202-877-2339; fax: þ1-202-877-9393.
E-mail: Christopher.Barnett@Medstar.net
See page 295 for disclosure information.
https://doi.org/10.1016/j.cjca.2019.01.005
0828-282X/Ó 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

RESUM 
E
Il est important de reconnaître l’hypertension arte rielle pulmonaire
(HTAP) associe e au virus de l’immunode ficience humaine (VIH)
compte tenu de son lien avec une morbidite  et une mortalite e leve
es.
e des antire
L’arrive troviraux a fait en sorte que l’attention se porte
desormais bien plus sur la prise en charge des complications car-
diopulmonaires chroniques que sur le traitement des infections
opportunistes imputables à une immunode ficience. Les symptômes
tant aspe
e cifiques, l’indice de suspicion clinique doit être e leve pour
viter des retards indus dans le diagnostic de l’HTAP associe
e e au VIH.
Bien que plusieurs prote ines virales aient e
 te
 incrimine es dans la
pathogenèse de cette affection, son me canisme exact reste ne buleux.
Il faudra re aliser de nouvelles e tudes pour e lucider les processus
pathologiques en cause, pour trouver des outils permettant un diag-
nostic pre coce et de couvrir de nouvelles cibles the rapeutiques afin
d’ame liorer le pronostic de cette grave complication.
from the 2018 6th World Symposium of Pulmonary
Hypertension include a revised definition of PAH; the
concomitant presence of mPAP > 20 mm Hg, PAWP  15
mm Hg, and pulmonary vascular resistance (PVR) of
3
Wood units.7 Implementation of this definition will result in
reclassification of HIV-PAH. Many patients who would not
have previously met the diagnostic criteria will meet the
revised criteria. The effects of this new definition of PAH on
diagnosis and treatment of HIV-PAH will undoubtedly have
significant effects on the epidemiology and treatment of HIV-
PAH that will emerge in the next decade.
PH is classified clinically into 5 different categories based
on pathologic similarities and hemodynamic characteristics
(Table 1).7 HIV-PAH is the most common form of PH in
HIV-infected patients. However, PH associated with left heart
disease and lung disease are expected to increase with the
expected increase in common chronic cardiac8 and respira-
tory9 diseases in an aging population with concurrent HIV. It
is important to note that the hemodynamics profile of group 1
PAH is identical to groups 3, 4, and in some cases 5 and even
2.10 It is also common that patients with PAH have comorbid
conditions (ie, a patient with HIV-PAH who has comorbid
smoking-related obstructive lung disease with hypoxemia) that
may also contribute to elevated pulmonary artery pressures
(PAPs). Therefore, it is critically important that each patient
Basyal et al.
Pulmonary Hypertension in HIV
Table 1. Classification of pulmonary hypertension
Clinical classification of PH
1. PAH
1.1 Idiopathic
1.2 Heritable
1.3 Drug and toxin induced
1.4 Associated with
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 Long-term responders to calcium channel blockers
1.6 With overt features of venous/capillary (pulmonary veno-occlusive
disease or pulmonary capillary hemangiomatosis) involvement
1.7 Persistent PH of the newborn
2. PH due to left heart disease
2.1 Heart failure with preserved left ventricular ejection fraction
2.2 Heart failure with reduced left ventricular ejection fraction
2.3 Valvular disease
2.4 Congenital/acquired cardiovascular conditions leading to
postcapillary PH
3. PH due to lung disease or hypoxia
3.1 Obstructive lung disease
3.2 Restrictive lung disease
3.3 Other lung diseases with mixed restrictive/obstructive pattern
3.4 Hypoxia without lung disease
3.5 Developmental lung disease
4. Chronic thromboembolic PH
4.1 Chronic thromboembolic PH
4.2 Other pulmonary artery obstructions
5. PH with unclear or multifactorial mechanisms
5.1 Hematologic disorders
5.2 Systemic disorders and metabolic disorders
5.3 Others
5.4 Complex congenital heart disease
HIV, human immunodeficiency virus; PAH, pulmonary arterial hyper-
tension; PH, pulmonary hypertension.
undergoing evaluation for possible HIV-PAH undergo a
complete diagnostic evaluation to identify all causes of
elevated PAP and that the hemodynamic profile of the patient
be considered in this context to determine the correct diag-
nosis and the appropriate course of treatment.11
Epidemiology
The generally accepted prevalence of HIV-PAH is 0.5% of
HIV-infected individuals. The initial prevalence estimate of
0.5% came from a large Swiss cohort of 1200 untreated patients
with HIV who were evaluated with transthoracic echocardi-
ography for unexplained respiratory symptoms.12 This was a
hypothesis-generative prospective cohort study of consecutive
patients with HIV infection who presented with respiratory
symptoms over a 9-month period. Of the 74 patients with
respiratory symptoms, echocardiography was performed in 12
patients, and 6 were found to have right ventricular systolic
pressure of between 49 and 64 mm Hg plus right atrial pressure,
as well as other echocardiography findings of right heart failure.
RHC was not performed in this cohort. Despite the significant
limitations of this study design, the estimated 0.5% prevalence
of HIV-PAH was remarkably high in comparison with the
prevalence of PAH in the general population, which has been
estimated to be 5 to 25 cases per million.13
The 0.5% prevalence estimate was later confirmed in a
prospective study of 7648 patients with HIV in France.14 In
289
this study, patients with unexplained dyspnea were evaluated
with echocardiography and, if found to have a tricuspid
regurgitant velocity (TRV) greater than 2.5 m/s, subsequent
RHC was performed. A total of 18 patients underwent RHC,
and PAH was confirmed in 5. When added to the 30 patients
in the cohort previously diagnosed with HIV-PAH, this led to
a prevalence of 0.46% (95% confidence interval, 0.32-0.64).
Of note, this well-designed study was performed from 2004 to
2005 after introduction of ART. The estimate of 0.5% is
unchanged from the initial Swiss cohort supporting a
conclusion that treatment of HIV-infected patients with ART
did not change the prevalence of HIV-PAH. Also, patients in
this study underwent RHC and met the rigorous invasive
hemodynamic criteria for a diagnosis of PAH, so the estimate
of 0.5% does not include patients with elevated PAP sec-
ondary to other non-PAH processes.
At the end of 2016, there were approximately 36.7 million
people living with HIV and acquired immunodeficiency
syndrome worldwide. By using the estimated prevalence of
0.5%, there may be as many as 183,500 patients with HIV-
PAH worldwide.
Other studies using echocardiography to estimate the
prevalence of HIV-PAH have reported rates of HIV-PAH as
high as 2.6% to 14%.15-18 However, echocardiographic esti-
mates of PAP are known to be inaccurate when compared
with RHC-measured PAP, so it is possible that echocardio-
graphic studies overestimate the prevalence of HIV-PAH. For
example, in the French study described,14 of 18 patients with
elevated PAP on the echocardiogram, PAH was confirmed
during RHC in only 5 (28%). However, it is also possible that
differences in prevalence in the studies described next are
related to differences in population studies, genetic suscepti-
bilities, use of stimulants, or mode of HIV transmission.
A study of 196 HIV-infected patients in San Francisco
found a pulmonary artery systolic pressure (PASP) > 30 mm
Hg in 35.2% of patients compared with 7.7% of controls.
After adjustment for injection drug use, stimulant use,
smoking, age, and gender, HIV-infected patients had a 7.0-
fold greater odds of having a PASP > 30 mm Hg (P <
0.001).19 Another echocardiography study of 656 patients
with HIV from Rhode Island, Colorado, Minnesota, and
Missouri showed that 23% had PASP > 30 mm Hg. How-
ever, there was also a high rate of left heart abnormalities
including systolic and diastolic dysfunction and left atrial
enlargement, all of which suggest a diagnosis of group 2 PH
from left heart disease might be contributing to elevated PASP
in this cohort.20 Two cohort studies of HIV-infected patients
in Spain reported a echocardiographically estimated PASP >
35 mm Hg in 9.9%16 and 9.8%15 of subjects. A retrospective
study in patients attending an HIV clinic at the National
Institutes of Health Clinical Center found that 9.3% patients
had TRV 2.5 m/s or higher (PASP 30 mm Hg) and 0.4% had
a TRV of at least 3 m/s (PASP 41 mm Hg).2 It has been
hypothesized that HIV-PAH may be particularly important in
Africa, where there may be a growing population of HIV
infection at risk for cardiovascular complications of HIV. A
meta-analysis of 3 studies performed in South Africa,
Tanzania, and Cameroon found a prevalence of
echocardiography-estimated PASP > 35 mm Hg of 14%
(95% confidence interval, 6-23) in a pooled sample of 664
individuals.18
290
Figure 1. Pathologic appearance of a normal pulmonary arteriole compared with a pulmonary arteriole in pulmonary arterial hypertension (PAH). (A)
Normal pulmonary arteriole. (B) Pulmonary arteriole from a patient with PAH demonstrating vascular endothelial cell proliferation and smooth
muscle cell hypertrophy and a plexiform lesion. Reproduced from Barnett and De Marco10 with permission from Elsevier.
Pathogenesis
Patients with HIV-PAH have histological manifestations
indistinguishable from those found in patients with idiopathic
PAH. All forms of PH have common pathologic features
indicative of pulmonary vascular remodelling, which include
medial hypertrophy of muscular and elastic arteries, dilation,
and intimal atheromas of elastic pulmonary arteries.21 PAH is
characterized by the additional findings of constrictive and
complex arterial lesions. The hallmark of PAH is the plexi-
form lesion, a complex arterial lesion, characterized by focal
proliferation of endothelial cells lined by myofibroblasts,
smooth muscle cells, and connective tissue matrix (Fig. 1).22
In patients with pulmonary veno-occlusive disease, patho-
logic changes in the pulmonary venules are found in addition
to typical arteriolar pathology, and several case reports have
described findings of pulmonary veno-occlusive disease in
HIV-infected patients.23
The mechanisms by which HIV causes PAH remain
poorly understood. There is no evidence that HIV directly
infects pulmonary artery endothelial cells, and HIV nucleic
acids are not found in pulmonary vessels of human lung tis-
sues.24,25 Instead, HIV viral proteins probably play key roles
in PAH-associated vascular remodelling by causing prolifera-
tion of vascular endothelial cells, induction of inflammation,
oxidative stress, and deregulation of apoptosis (Fig. 2). In
support of this, pulmonary vascular remodelling was shown to
develop in the presence of HIV-1 proteins without an active
infection, leading to PH in a noninfectious HIV-transgenic rat
model.26 The presence of viral proteins, coupled with hyp-
oxia, also has been shown to synergistically increase the PAPs
in a transgenic animal model.27
HIV-1 gp 120 envelope glycoprotein, a protein detected in
screening tests for HIV, contributes to the development of
HIV-PAH by induction of apoptosis, increased endothelial
cell permeability, and increased secretion of endothelin.28,29
Endothelins are potent vasoconstricting peptides that are
Canadian Journal of Cardiology
Volume 35 2019
also responsible for inflammation, cell proliferation, and
fibrosis, with isoform endothelin-1 being a well-established
mediator of pulmonary vascular homeostasis.30 Plasma levels
of endothelin-1 have been shown to be higher among HIV-
infected patients with elevated PASP than among uninfected
controls and were independently associated with higher values
of PASP by echocardiography and RHC.31
The Nef protein is a viral protein important for in vivo
viral replication. Several studies suggest that Nef plays a key
role in the pathogenesis of HIV-PAH. Complex plexiform-
like lesions were found in macaques infected with chimeric
virions expressing human HIV Nef in a simian immunode-
ficiency virus (SIV) genetic backbone (SHIV) Nef but not in
animals infected with SIV. The same study also showed co-
localization of HIV Nef protein in the pulmonary endothe-
lial cells.32 Specific Nef signature sequences have been
Chronic IV drugs
inflammaon (cocaine)
HIV Viral Proteins
gp-120 Inflammatory mediators Viruses
tat
Nef
Pulmonary Vascular
Remodeling
Pulmonary arterial
Hypertension
Figure 2. Pathogenesis of human immunodeficiency virus (HIV)-
associated PAH. IV, intravenous; Tat, transactivator of transcription.
Basyal et al.
Pulmonary Hypertension in HIV
associated with PAH in 2 different HIV cohorts.33 Further, a
recent analysis of SHIV Nef-infected macaques showed
findings that included cardiac hypertrophy, increased inter-
leukin (IL)-2 and granulocyte macrophage colony-stimulating
factor, and inhibition of bone morphogenic protein receptor-2
(BMPR2).34
Bone morphogenic proteins signal through BMPR2 to
regulate cellular differentiation, proliferation, and apoptosis.
Mutations leading to loss of function or reduction in BMPR2
expression are known to cause PAH.35 HIV viral proteins alter
the BMPR signalling pathway leading to PAH. Transactivator
of transcription (Tat) is an HIV viral protein that has been
shown to repress transcription of BMPR2 in macrophages
with downstream decreased phosphorylation of receptor-
associated SMAD causing overall repression of BMPR2-
SMAD signalling cascade.36 Tat is also implicated in
significantly increasing levels of the proinflammatory cyto-
kine, IL-6, which causes deleterious smooth muscle prolifer-
ation and adverse remodelling of the pulmonary vascular
architecture.
Injection drug use has been implicated in the pathogenesis
of HIV-PAH.37 Rhesus macaques infected with SIV that were
concurrently treated with intramuscular morphine developed
adverse vascular remodelling, including plexiform lesions that
typify PAH. Control animals that received morphine or were
infected with SIV did not demonstrate pathologic endothelial
proliferation or vascular obliteration.38
Cocaine synergizes with HIV-Tat to promote proliferation
of pulmonary artery smooth muscle cells.39 The BMPR2 axis
appears to be the target of stimulant drugs as significant
downregulation of BMPR expression has also been shown in
the lung tissue of HIV-infected injection drug users compared
with HIV-infected non-drug users or uninfected intravenous
drug users.40
HIV infection induces a state of chronic inflammation
characterized by persistent immune activation and dysregu-
lation,41 which likely indirectly induces release of proin-
flammatory cytokines and growth factors that could produce
PAH.42 Chronic inflammation persists even with effectively
treated HIV infection and is independently associated with
increased cardiovascular risk.43 Asymmetric dimethyl arginine,
a marker of nitric oxideemediated endothelial dysfunction,
accumulates with chronic inflammation and independently
predicts HIV-PAH.44,45 Various growth factors have been
implicated in the development of HIV-PAH: Hypoxia
inducible factor 1 alpha appears to mediate the response to
viral proteins gp120 and Tat,26 platelet-derived growth factor
is a potent stimulus of smooth muscle cell and fibroblast
growth and migration,46 and vascular endothelial growth
factor A induces vascular permeability and endothelial cell
proliferation.47 In addition, Tat protein causes increased
endothelial cell permeability and injury via production of IL-6
shown to be present in lungs of patients with severe PH.
Biomarkers of fibrosis (ST-2), inflammation (high-sensi-
tivity C-reactive protein), thrombosis (D-dimer), apoptosis
(growth and differentiation factor [GDF]-15), and myocardial
injury (high-sensitivity troponin I and N-terminal proe
B-type natriuretic peptide) are elevated in patients with HIV.
In particular, ST-2, GDF-15, high-sensitivity C-reactive
protein, and D-dimer appear to independently predict all-
cause mortality irrespective of whether patients are on
291
ART.48 Eight biomarkers were evaluated in a cluster analysis
of 332 HIV-infected patients, which showed that serum
biomarkers can be used to classify patients with HIV into
separate clusters that can predict structural and functional
abnormalities and mortality.49
A role for other viruses in the pathogenesis of HIV-PAH
has been hypothesized. Evidence of human herpesvirus 8
plexiform lesions of patients with PAH initially suggested a
possible role for human herpesvirus 8 in the pathogenesis of
PAH;50 however, this finding was not recapitulated in other
populations.51 Upregulation of human endogenous retrovirus
K could induce and perpetuate chronic immune dysfunction
and endothelial dysfunction, leading to adverse remodelling
related to PAH, and HIV could be a potential activator of
human endogenous retroviruses.52
Clinical Presentation
HIV-PAH presentation is clinically indistinguishable from
idiopathic PAH and presents with nonspecific and often
insidious symptoms. As a result, diagnosis is often delayed
because these nonspecific symptoms are often attributed to
HIV infection or other common complications of HIV
infection. The time from symptoms onset to diagnosis in
HIV-PAH is only approximately 6 months, which is shorter
than 2.5 years in patients with idiopathic PAH53 and could be
related to closer follow-up or more rapid clinical deterioration
and symptom development in HIV-PAH.54 However, a
recent study of patients with HIV discharged from hospitals in
the United States between 2001 and 2010 found that the
reported prevalence of HIV-PAH in hospitalized HIV-
infected patients was 0.04% to 0.015%, much lower than
the expected prevalence of 0.5%.55 This may indicate that the
diagnosis of HIV-PAH is being missed and reinforces the
importance of careful history taking to identify patients with
dyspnea or exercise intolerance that is unexplained, as well as
appropriate follow-up evaluation.
A meta-analysis of published cases of HIV-PAH performed
in 2000 found that the most common presenting symptom in
HIV-PAH was progressive shortness of breath (85%) followed
by pedal edema (30%), nonproductive cough (19%), fatigue
(13%), syncope or near syncope (12%), and chest pain (7%).
Findings on examination may include signs of PH and right
heart failure, including a loud P2 component of the second
heart sound, a right sided S3 gallop, murmurs of tricuspid and
pulmonic regurgitation, increased jugular venous pressure,
and peripheral edema.22 Abnormal findings on lung exami-
nation may suggest an alternative diagnosis because lung ex-
amination results are usually normal in patients with PAH.
The chest radiograph may show supportive, but nonspecific
findings such as cardiomegaly and prominence of the pul-
monary arteries. Likewise, the electrocardiogram may show
right ventricular hypertrophy, right axis deviation, right atrial
abnormality, or sinus tachycardia.
Diagnosis
Until recently, it was recommended that HIV-infected
patients without a clinical suspicion of PAH undergo
echocardiographic screening for PAH because it is not cost-
effective.56 However, this recommendation was updated
292
Figure 3. BlandeAltman analysis demonstrating lack of agreement
between the Doppler echocardiogram-estimated pulmonary artery
systolic pressure (PASP) and right heart catheterization (RHC)-
measured PASP. PA, pulmonary artery; PVR, pulmonary vascular
resistance. Reproduced from Selby et al.61 with permission from
Wolters Kluwer Health, Inc.
during the 2018 6th World Symposium of Pulmonary Hy-
pertension. The new recommendation is for echocardio-
graphic screening of HIV-infected patients with one of the
following risk factors: female sex, intravenous drug use/
cocaine use, hepatitis C virus infection, origin from a high-
prevalence country, known Nef or Tat HIV proteins, and
US African-American patients independent of symptoms.57
Evaluation of HIV-PAH is similar to that of HIV-negative
patients with suspected PAH. All patients require a
Asymptomac
Peak Cardiac Output
Cardiac Output
Resng PA Pressure
Figure 4. Schematic representation of changes in haemodynamic parameters over the course of PAH.
Canadian Journal of Cardiology
Volume 35 2019
comprehensive evaluation to identify all potential contrib-
uting factors to elevated PASP, including identification of
other conditions that cause group 1 PAH and any conditions
that could cause group 2, 3, 4, or 5 PH according to guideline
recommendations. When evaluating HIV-infected patients
with respiratory symptoms, it is also important to consider
and exclude all non-PAH causes of these symptoms.
Echocardiography is usually the first test to be performed if
HIV-PAH is suspected. PASP is estimated from Doppler-
estimated velocity of the systolic regurgitant jet across the
tricuspid valve, then entering the value into the modified
Bernoulli equation to estimate the pressure gradient between
the right atrium and right ventricle, and then adding the
estimated right atrial pressure to determine the total PASP.58
Compared with invasive hemodynamics, Doppler estimates of
PASP have been shown to be inaccurate in both the general
and PAH populations59,60 and in patients with HIV-PAH.61
In a study of use of Doppler echocardiography to assess PASP
in an HIV-infected cohort, Doppler estimates of PASP were
inaccurate in 19.7% of patients and 1 in 3 patients with a
diagnosis of HIV-PAH were missed (Fig. 3).61 Thus, esti-
mation of PASP alone by echocardiography is not sufficient to
definitely rule out PAH.
In addition to PASP, echocardiography provides other
important data points in the evaluation for PAH. These
additional findings should be incorporated into the assessment
of the clinical suspicion for PAH in HIV-infected patients.
Proceeding with invasive hemodynamic evaluation is often
appropriate in patients who do not have elevated echo-
cardiographically estimated PASP but do have other echo-
cardiographic findings that occur secondary to PAH.
Pulmonary artery acceleration time as measured by pulsed-
wave Doppler analysis and can be used to estimate PASP
independently of tricuspid regurgitation, and it can be espe-
cially useful in cases when tricuspid regurgitation is
Progressive Advanced
PVR
Pulmonary Vascular Resistance
Resng Cardiac Output
Time
Basyal et al. 293
Pulmonary Hypertension in HIV

insufficient to estimate PASP.62 Studies of right ventricular

outflow Doppler flow velocity envelopes can provide useful
insight into hemodynamics. Mid-systolic flow deceleration
and notching have been associated with higher PAP, higher
PVR, and worse outcomes.63,64 Evaluation for right heart
chamber enlargement, systolic dysfunction, and paradoxical
septal motion are important in the evaluation of the severity
and prognosis of HIV-PAH.65 Echocardiography is also
helpful to exclude secondary causes of PH, including left
ventricular systolic dysfunction and clinically relevant valvular
diseases.66
RHC is the gold standard for the hemodynamic evaluation
of PH.67 Hemodynamic assessment with RHC is mandatory
before the initiation of PAH-specific therapy. It should be
performed by a clinician with expertise in hemodynamic
assessment and diagnostic evaluation for patients with PH to
minimize complications and optimize data collection.68
Guidelines and recommendations for the optimal perfor-
mance of RHC have been published.6,11 During RHC for
suspected PAH, measurements should include the PAP, right
atrial pressure, cardiac output, and PAWP, as well as the
calculated cardiac index and PVR. A complete hemodynamic
assessment including assessment of the cardiac output and
PVR is required because the PAP in isolation is inadequate to
make the diagnosis of PAH or assess prognosis. As PAH
progresses and the right ventricle fails and can no longer
generate pressure, PAP will decrease (Fig. 4). However, car-
diac output in this case will be reduced, and the resulting PVR
will be very elevated. Measurement of the PAWP is used as an
estimate of left ventricular filling pressures, but it may be
difficult to obtain a good-quality PAWP in some patients.
Measurement of the left ventricular end-diastolic pressure Figure 5. KaplaneMeier estimate (A) of overall survival in patients
with PAH-HIV and (B) of survival stratified by baseline New York Heart
(LVEDP) should be performed whenever a reliable PAWP
Association (NYHA) class. Survival was calculated from the time of
tracing cannot be obtained or the value of the PAWP is PAH diagnosis to the end of follow-up. FC, functional class. Reprinted
inconsistent with the expected value based on the clinical with permission from Degano et al.70 with permission from Wolters
picture. When an LVEDP is obtained, it should be Kluwer Health, Inc.
substituted for the PAWP in calculation of the PVR. Routine
vasodilator testing is not recommended in patients with sus-
pected HIV-PAH because positive vasodilator testing rarely is
found in patients with HIV-PAH. Additional provocative 27% to 66%.22,53,69,71 One study of 20 HIV-infected pa-
testing such as assessment of exercise hemodynamics or tients with PH reported survival rates of 46% at 2 years,72 and
changes in hemodynamics after fluid challenge may be another study of 19 patients with HIV-PAH reported survival
considered in patients with characteristics suggesting PH rates of 58% at 1 year, 32% at 2 years, and 21% at 3 years
secondary to left heart disease; however, interpretation of re- with median survival of 1.3 years.73 A larger longitudinal
sults in this setting can be challenging.57 In patients who are study of 82 consecutive patients from 1986 to 2000 showed
at risk for coronary artery disease, performance of coronary survival rates at 1, 2, and 3 years was 73%, 60%, and 47%,
angiography at the time of RHC may be appropriate. respectively.53 This study also showed that higher New York
Heart Association (NYHA) functional class predicted a poor
outcome. Factors associated with an improved outcomes
Prognosis included higher CD4 cell count, use of ART, and treatment
In patients with HIV, the development of PAH is an in- with epoprostenol (Fig. 5).
dependent predictor of death and has often been associated Some recent studies have shown improved HIV-PAH
with poor survival.69 Common causes of death in HIV-PAH survival rates that some authors have hypothesized is a result
are attributed to consequences of PH, including right heart of treatment with ART in addition to treatment with PAH
failure and sudden death (57%-71%).22,53,70 therapies. A retrospective review of 77 consecutive patients
The effects of ART on the development and prognosis of between 2000 and 2008 showed that overall survival rates at
HIV-PAH remain controversial, and available data are inad- 1, 2, 3, and 5 years were 88%, 84%, 72%, and 63%,
equate to determine clearly the effect of ART on HIV-PAH. respectively.70 Consistent with prior studies, survival was
Before the era of ART and development of PAH-specific worse for patients in NYHA class IV. Factors related to poor
drugs, prognosis for HIV-PAH was extremely poor with HIV control (low CD4þ lymphocyte count and detectable
early studies showing high short-term mortality ranging from viral load) and factors related to increased severity of PAH
294
(clinical right heart failure, NYHA functional class IV, and
cardiac index < 2.8 L/min/m2) were associated with poor
survival on univariate analysis. A low cardiac index and low
CD4 count were independently related to poor survival on
multivariate analysis. A recent report from the REVEAL
registry showed that survival in HIV-PAH may be better than
that of other forms of PAH. In this large U.S. registry of PAH,
patients’ survival in HIV-PAH was 93%, 75%, and 64%
compared with idiopathic PAH survival of 88%, 74%, and
64% at 1, 3, and 5 years, respectively.74 There have also been
several published reports of patients with HIV-PAH who had
persistently normal hemodynamics even after cessation of
PAH therapy.75
Treatment
The approach to treatment of HIV-PAH is extrapolated
from larger studies of mixed group 1 patients with PAH
because there are few studies evaluating patients with HIV-
PAH alone.
Antiretroviral treatment
Current guidelines recommend that all patients with HIV
should be offered ART regardless of their CD4 cell count or
viral load.76 Therefore, all patients with HIV-PAH should be
treated with ART. Whether or not ART confers any hemo-
dynamic or outcomes benefits for those with HIV and PAH
remains controversial.77
In a retrospective analysis of 1042 HIV-infected patients,
PAH was significantly more frequent in patients treated with
ART than in those treated only with nucleoside reverse
transcriptase analogs.78 However, this difference may be due
to better knowledge of PAH as a complication of HIV
infection. Indeed, other retrospective studies have shown that
antiretroviral treatment is beneficial with reduced incidence of
PAH in patients treated with ART.71,78 A review of 509 cases
of HIV-PAH reported in the literature from January 1987 to
January 2009 showed that survival rates were higher for pa-
tients treated with ART (55% vs 22%, P < 0.01), patients
treated with PAH-specific therapy (76% vs 32%), and pa-
tients treated with ART and PAH-specific therapy (69% vs
38%, P < 0.01).77
The effects of ART on functional and hemodynamic pa-
rameters in HIV-PAH are controversial. A retrospective
analysis of 47 patients in the Swiss HIV cohort study showed
significant beneficial effects on the PASP and improvement in
NYHA functional class in patients with HIV-PAH treated
with ART.71 Another study reported that ART improved
right ventricular systolic pressureeright atrial pressure
gradient measured by echocardiography.73 The lack of
confirmatory diagnosis using RHC was a significant limitation
of these studies. When RHC was used for evaluation, ART
was associated with improved exercise tolerance assessed by 6-
minute walk distance without change in hemodynamic
parameters.70
The best evidence for the effects of ART on HIV-PAH
comes from the large prospective French cohort study of
HIV-PAH prevalence after treatment with ART became
routine. The finding that the prevalence was unchanged
supports a conclusion that ART does not affect the develop-
ment of HIV-PAH.14 The equipoise surrounding the effect of
Canadian Journal of Cardiology
Volume 35 2019
ART on HIV-PAH is redundant given that ART remains
central in standalone HIV management.
General measures
General principles of management of PH apply to patients
with HIV-PAH. Diuretics should be used for volume overload
with adjustment to maintain right-sided filling pressures as
near to normal as possible. Supplemental oxygen should be
used to correct hypoxemia because hypoxemia can exacerbate
pulmonary vasoconstriction and worsen PH. A favourable
response to vasoreactivity testing in patients with HIV-PAH is
rare, and calcium channel blockers should be used only in
carefully selected patients with close monitoring for worsening
symptoms and hemodynamics.79
PAH-specific therapy
Although patients with HIV are under-represented in
studies of PAH-specific therapy, a systematic review of HIV-
PAH treatment suggested a significant benefit to PAH-specific
therapy.77 In fact, normalization of hemodynamics with
PAH-specific therapy, which is rare in PAH from other cau-
ses, has been reported.80 The approach to using PAH-specific
therapies in HIV-PAH is largely extrapolated from studies of
PAH-specific therapies in other causes of group 1 PAH. PAH-
specific therapies should be used in patients with HIV-PAH
according to current PAH treatment guidelines.80 Because
the prognosis of HIV-PAH is poor, aggressive early treatment
with parenteral prostanoids as well as upfront double or triple
combination therapy may be appropriate. In patients who do
not respond to PAH-specific therapies, lung transplantation
may be considered.81 Current guidelines recommend that
patients with PAH be managed at or in collaboration with a
PAH expert referral center.80 This may be particularly
important in patients with HIV-PAH given the potential for
important drug interactions between ART and PAH-specific
therapies.
Phosphodiesterase inhibitors
Experience with phosphodiesterase type 5 inhibitors in
HIV-PAH comes from case reports and case series that report
improvements in dyspnea, NYHA functional class, exercise
capacity, and mean PAP.82 Possible interactions with ART
must be kept in mind when prescribing phosphodiesterase
type 5 inhibitors. The metabolism of sildenafil and tadalafil is
mediated by cytochrome P450 CYP 3A4 and CYP 2C9,
which are inhibited by protease inhibitors including ritonavir.
Marked increases in sildenafil levels have been observed dur-
ing co-administration with indinavir, saquinavir, and ritonavir
leading to the recommendation against co-administration with
sildenafil. However, this finding is of uncertain clinical sig-
nificance because it has not been associated with hypotension
or adverse effects in pharmacokinetic studies.83 Successful co-
administration of ritonavir and sildenafil in patients with
HIV-PAH have been reported.84 Tadalafil levels are less
affected by ritonavir, and guidelines suggest only close
monitoring if tadalafil therapy is initiated.85
Basyal et al.
Pulmonary Hypertension in HIV
Endothelin receptor antagonists
Bosentan, ambrisentan, and macitentan are endothelin
receptor antagonists used in the management of PAH.
Endothelin receptor antagonists improve hemodynamics and
exercise tolerance, and prevent worsening of PH. A prospec-
tive study of 16 patients with severely symptomatic (NYHA
class III-IV) HIV-PAH showed that 16 weeks of treatment
with bosentan improved clinical and hemodynamic parame-
ters, including improvement in 6-minute walk distance by 91
 60 m (P < 0.001), NYHA functional class by at least
1 class in 14 patients, increase in cardiac index by 39%,
decrease in mPAP by 21%, decrease in PVR by 43%, and
improved quality of life.86 An open-label study of bosentan
with ART compared with ART alone also showed improve-
ment in exercise capacity and cardiopulmonary hemodynamic
parameters at 24 weeks.87 These short-term improvements
were found to be sustained long term in a study of bosentan in
HIV-PAH that followed 59 patients over 29 months and
showed long-term improvement in symptoms, exercise toler-
ance, and hemodynamic parameters.88 In addition, it showed
improved survival with survival rates of 93%, 86%, and 66%
at 1, 2, and 3 years, respectively, with normalization of he-
modynamic parameters in 10 of 59 patients. In all these
studies, bosentan was observed to be safe and overall well
tolerated in conjunction with ART with no adverse effects on
control of HIV infection.
Large studies of ambrisentan and macitentan that resulted
in Food and Drug Administration approval in PAH included
only small numbers of patients with HIV.89,90 However, use
of bosentan has largely been supplanted by ambrisentan and
macitentan because of the lower frequency of liver function
test abnormalities and fewer drug interactions with ART.91
Prostacyclin analogues
Prostacyclin analogues can be administered through
various routes, including intravenous, subcutaneous, inhaled,
or oral. Use of short-term epoprostenol infusions was shown
to reduce total PVR by 20% in a study of 19 patients with
HIV-PAH.72 Other smaller case series of 2 patients92 and 6
patients93 showed improvements in PAP, PVR, and cardiac
output. In the latter study, the benefits were sustained over
longer-term follow-up. In an uncontrolled trial of 8 patients
with HIV-PAH, inhaled iloprost resulted in acute improve-
ment of PVR and confidence interval. Hemodynamic
improvement persisted and exercise capacity also improved in
4 patients who continued with long-term iloprost.94 Selexipag
is a novel prostacyclin receptor agonist that was studied in
1156 patients in a phase 3 randomized controlled trial.
However, only 10 patients with HIV-PAH were included, so
it is difficult to draw specific conclusions about its use in HIV-
PAH.95
Future Directions
Diagnosing HIV-PAH and initiating treatment early are
the fundamental goals in managing this condition successfully.
It is possible that the high prevalence of elevated PASP in the
echocardiography studies described could be early or mild
HIV-PAH and might identify patients at high risk for
developing HIV-PAH in whom early treatment might
295
beneficial. However, screening for HIV-PAH is currently not
recommended, and treatment of patients with HIV who have
mPAP < 25 mm Hg is not recommended given the uncertain
significance of mild elevations of PASP and uncertain benefits
of treatment in these patients.
New diagnostic tools may better identify patients with
HIV-PAH or those at risk of developing HIV-PAH. A single-
center prospective observational study aims to use exercise
magnetic resonance imaging in conjunction with cardiopul-
monary testing to identify HIV-positive patients with elevated
PASP on echocardiography who will undergo rest and exercise
magnetic resonance imaging evaluation over 24 months to
define longitudinal progression of disease.96 Novel biomarkers
also may aid in the identification of patients with HIV-PAH
who are at risk of a poor outcome. HIV-positive patients with
elevated levels, the biomarker ST2, N-terminal proeB-type
natriuretic peptide, and GDF-15 were shown to have a 67%
increased risk of elevated PASP on echocardiography and 3.1-
fold higher mortality compared with patients with HIV
without elevations in these markers.49 Further study is needed
to determine if these approaches to diagnosis result in better
outcomes for patients.
Conclusion
HIV-PAH is an important complication of HIV that re-
sults in significant mortality and mortality. Although incom-
pletely understood, HIV proteins and chronic immune
activation seem to play a significant role. Incorporating
advanced imaging modalities and biomarkers may help us
promptly detect and treat cases of HIV-PAH earlier. PAH-
specific therapy remains the cornerstone of management,
and potential for drug interactions must be kept in mind.
Further studies are needed to understand the pathogenesis of
HIV-PAH to find optimal targets for treatment.
Disclosures
The authors have no conflicts of interest to disclose.
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